The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor genetic sequences. A variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the circumstances. For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal. In many cases, both progenitor and variant forms survive and co-exist in a species population. The coexistence of multiple forms of a genetic sequence gives rise to genetic polymorphisms, including single nucleotide polymorphisms, otherwise known as “SNPs”. SNPs can also arise in areas of the genome with no apparent function, but the SNP can be genetically linked to a variant sequence in the genome. Thus, the SNP can closely correlate with the variant sequence of the genome, depending on how close the genetic linkage is.
Approximately 90% of all polymorphisms in the human genome are SNPs. SNPs are single base positions in DNA at which different alleles, or alternative nucleotides, exist in a population. The SNP position (interchangeably referred to herein as SNP, SNP site, or SNP locus) is usually preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the populations). An individual may be homozygous or heterozygous for an allele at each SNP position.
Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous. Some believe the patient response is due to their genetic make-up, which results in having altered receptors, enzymes, or some change in cell physiology. Thus, the difference in genetic make-up results in a different response from others in the population. As such, researchers have expressed hope that the nucleic acid sequences of a patient can be used in pharmaceutical research to assist the drug development and selection process. To date, it is our belief that use of the nucleic acid sequence of a patient in pharmaceuticals has not been applied to immune tolerance.
Immune or immunological tolerance is the process by which the immune system does not mount an immune response to an otherwise immunogenic antigen, or has its immune response redirected in a suppressive manner. Acquired or induced tolerance refers to the immune system's adaptation to external antigens characterized by a specific non-reactivity of the lymphoid tissues to a given antigen that in other circumstances would likely induce cell-mediated or humoral immunity. One of the most important natural kinds of acquired tolerance occurs during pregnancy, where the fetus and the placenta must be tolerated by the maternal immune system. There are numerous models for the induction of tolerance, including use of the eutherian fetoembryonic defense system and induction of tolerance primarily requires the participation of regulatory T cells.
One specific type of immune tolerance, oral tolerance, is the specific suppression of cellular and/or humoral immune reactivity to an antigen by prior administration of the antigen by the oral route, probably evolved to prevent hypersensitivity reactions to food proteins and bacterial antigens present in the mucosal flora. It is of immense immunological importance, since it is a continuous natural immunologic event driven by exogenous antigen. Due to their privileged access to the internal milieu, antigens that continuously contact the mucosa represent a frontier between foreign and self components. Oral tolerance evolved to treat external agents that gain access to the body via a natural route as internal components without danger signals, which then become part of self. Failure of oral tolerance is attributed to the development and pathogenesis of several immunologically based diseases, including Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis). Other common forms of tolerance induction contemplated in this invention include internasel and IV tolerance induction.
Today genomics is still not used to refine our medical management, despite the large quantities of research into the genome and SNPs. As such, there are few reliable wide-scale assays, kits and methods that examine an individual's genome to find inherited susceptibility, gene expression, and predicted pharmacogenomic response. More specifically, there is no use of genomics in the field of immune tolerance.
The inventors are credited with providing methods, reagents, kits and assays that merge genomics with immune tolerance. As such, the inventors are able to detect nucleic acid sequences, and based on the presence and/or absence of nucleic acid sequences; tailor a method of care for the patient who desires induction of immune tolerance. In one specific embodiment, the nucleic acid sequences of interest are SNPs.